A novel subtype of sporadic Creutzfeldt–Jakob disease with PRNP codon 129MM genotype and PrP plaques

Abstract

The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt–Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21–20 kDa (T121−20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.

Understanding Creutzfeldt-Jakob disease in Iran: a systematic review of case reports

“… 25 More research should be conducted on the role of the PRNP gene in different CJD subtypes to improve diagnosis, prognosis and potential treatments for prion diseases. 26 Hence, studying PRNP gene variations could aid in the prompt detection of CJD in future studies involving Iranian individuals exhibiting neurodegenerative symptoms.…”

Novel histotypes of sporadic Creutzfeldt–Jakob disease linked to 129MV genotype

“…Indeed, the proportion of 2C-K cases with high burden of cPrP exceeds 60%, whereas the proportion of 2C-K cases with a low burden of cPrP is only 27%. Another intriguing observation is the co-occurrence of T1 20 and T1 21 in sCJD [ 4 , 11 , 14 ]. T1 20 is by far the major T1 species in sCJDMV.…”

“…Denatured proteins were loaded onto 15% Tris–HCl SDS–polyacrylamide gels (W × L: 20 cm × 20 cm; Bio-Rad PROTEAN ® II xi cell system), and in 15% Tris–HCl precast gels (W × L: 13.3 cm × 8.7 cm; Bio-Rad Criterion™). Proteins were then transferred onto Immobilon PVDF membranes, blocked with blocking buffer (5% non-fat milk in Tris-buffered saline with Tween-20) and probed with antibodies 3F4 (1:10000), 1E4 (1 µg/ml) or tohoku-2 (1:10000) [ 4 , 7 ]. Membranes were washed with 1X TBS-T (1X TBS with Tween 20) and probed with a horseradish peroxidase conjugated goat anti-mouse or anti-rabbit antibody (1:3000).…”

“…PrP proteins were visualized on Kodak films by the ECL Plus as described by the manufacturer [ 8 , 9 , 12 ]. Western blot analysis of cases 23, 24, 26–28 (Additional file 1 : Table S1) was carried out using Odyssey near-infrared imaging system (LICOR Biosciences) [ 4 , 10 , 13 ].…”

“…Samples with larger PrP Sc amounts were diluted so that all cases had the same PrP Sc amount, which was determined by western blot analysis. RT-QuIC was carried out as previously described with some modifications [ 4 ]. Bacterially expressed, truncated (amino acids 90–231) Syrian hamster recombinant PrP (recHaPrP) was used as substrate; kinetic reactions were average of three reaction wells of sample with 10 –4 , 10 –6 , or 10 –8 dilution.…”